Table 1.
BBB breakdown in APP, PSEN1, Tau, and pericyte-deficient transgenic models
Mouse line, construct, promoterFindingsAgeRegionReferenceBrain AβCAANeurodegenerative and behavior changesReference
Tg APP models         
APPSw/0 (Tg2576), hAPP695, K670M/N671L, hPrP Fibrin perivascular deposits, BBB leakage of Evans blue 6 and 12 mo; not studied before 6 mo Cortex, hippocampus Paul et al., 2007  7–10 mo 9–12 mo 6–9 mo Hsiao et al., 1996; Domnitz et al., 2005; Kumar-Singh et al., 2005; Webster et al., 2014  
 Loss of BBB tight junctions,a LRP1 endothelial expression, PDGFRβ+ pericytes, VSMCs 18 mo; not studied before 18 mo Cortex Park et al., 2013a      
 IgG perivascular deposits, loss of CD13+ pericytes, endothelial degeneration 1, 3, 6, and 9 mo Cortex, hippocampus Sagare et al., 2013      
 IgG perivascular deposits, albumin perivascular deposits, microhemorrhages,b,c endothelial degeneration, pericyte degeneration, VSMC loss, swollen astrocytic end-feet 17 and 25 mo; not studied before 17 mo Cortex, hippocampus, thalamus Kumar-Singh et al., 2005      
 BBB leakage of Evans blue, BBB leakage of exogenous tracers 4 and 10 mo Cortex Ujiie et al., 2003      
 Loss of BBB tight junctionsa,d 18 and 24 mo; not studied before 18 mo Cortex, hippocampus Biron et al., 2011      
 Loss of LRP1 endothelial expression 4 and 6 mo Cortex, hippocampus, thalamus Deane et al., 2004      
 Increased RAGE vascular expression 9 mo; not studied before 9 mo Cortex, hippocampus Deane et al., 2003      
 Genetically increased LRP1 expression in brain microvessels 16 and 24 mo; not studied before 16 mo Cortex Bell et al., 2009  Slowed down Slowed down Not studied Bell et al., 2009  
APPSw/0; Pdgfrβ+/−, accelerated loss of pericytes IgG perivascular deposits, loss of CD13+ pericytes 1, 3, 6, and 9 mo Cortex, hippocampus Sagare et al., 2013  Accelerated, +tau pathology and loss of neurons Accelerated Accelerated Sagare et al., 2013  
APPSw/0; Slc2a1+/−, GLUT1 endothelial haploinsufficiency Fibrin perivascular deposits, IgG perivascular deposits, and loss of BBB tight junctions,a,d LRP1 endothelial expression, GLUT1 endothelial expression 2 wk and 1, 8–10, 12, and 16 mo Cortex, hippocampus Winkler et al., 2015  Accelerated, +loss of neurons Not studied Accelerated Winkler et al., 2015  
APPSw/0; mdr1a/b–/–, loss of Pgp endothelial function Loss of Pgp endothelial expression, BBB leakage of Pgp substrate, loss of LRP1 endothelial expression 2 and 3 mo Striatum, cortex, hippocampus Cirrito et al., 2005  Accelerated Not studied Not studied Cirrito et al., 2005  
APPSw/0; Picalm+/−, PICALM endothelial haploinsufficiency Loss of PICALM endothelial expression 3 mo Cortex, hippocampus Zhao et al., 2015b  Accelerated Accelerated Accelerated Zhao et al., 2015b  
APP V717F (PDAPP), hAPP full-length, V717F, PDGFb Fibrin perivascular deposits, BBB leakage of Evans blue 6 and 12 mo; not studied before 6 mo Cortex, hippocampus Paul et al., 2007  6–9 mo 10–12 mo 6 mo Paul et al., 2007; Webster et al., 2014  
PD-hAPP, hAPP minigene, V717F/K670M/N671L, PDGFb Blockade of RAGE 9 mo Cortex, hippocampus Deane et al., 2003  Slowed down Not studied Not studied Deane et al., 2003  
APPSwI (TgCRND8), hAPP695, K670M/N671L/V717F, hPrP Fibrin perivascular deposits, BBB leakage of Evans blue 6 and 12 mo; not studied before 6 mo Cortex, hippocampus Paul et al., 2007  3 mo 6–7 mo 3 mo Domnitz et al., 2005; Webster et al., 2014  
 Fibrin perivascular deposits 6 mo; not studied before 6 mo Cortex Chen et al., 2017      
APPSwDI, hAPP770, K670M/N671L/E693Q/D694N, mThy1 Albumin perivascular deposits 6 mo; not studied before 6 mo Dorsal subiculum Kruyer et al., 2015  3–6 mo 6 mo 3–6 mo Davis et al., 2004; Deane et al., 2004  
 Loss of LRP1 endothelial expression 4 and 6 mo Cortex, hippocampus, and thalamus Deane et al., 2004      
 Genetically decreased LRP1 expression in brain microvessels 16 and 24 mo; not studied before 16 mo Cortex Bell et al., 2009  Accelerated Accelerated Not studied Bell et al., 2009  
APPSw (APP23), hAPP751, K670M/N671L, mThy1 Microhemorrhages,b,c leukocyte infiltration 16 and 30 mo; not studied before 16 mo Cortex, thalamus Beckmann et al., 2011  6 mo 12 mo 3 mo Webster et al., 2014  
TetO-APPSwI, hAPP695, K670M/N671L/V717F, tetracycline-responsive promoter Microhemorrhages,b,c increased BBB permeability to iodinated contrast agent 14 mo; not studied before 14 mo Cortex, hippocampus, thalamus Tanifum et al., 2014  2–6 mo 14 mo Not studied Tanifum et al., 2014  
APPSwArc (ArcAβ), hAPP695, K670M/N671L/E693G, mPrP Microhemorrhagese and increased BBB permeability to gadolinium contrast agent 9 and 21 mo; not studied before 9 mo Cortex, hippocampus, olfactive bulb Klohs et al., 2011, 2013   6 mo 9–15 mo 6 mo Klohs et al., 2012  
APPSw/0; PSEN1ΔE9, m/hAPP695 K595N/M596L × hPSEN1dE9, mPrP Microhemorrhagesb,c 9 mo; not studied before 9 mo Cortex Kelly et al., 2015  6–7 mo 6 mo 6 mo Duff et al., 1996; Webster et al., 2014  
 Fibrin perivascular deposits 10 mo; not studied before 10 mo Hippocampus, periventricular zone McManus et al., 2017      
APPSw/0; PSEN1M146L, hAPP695 K670M/N671L × PSEN1 M146L, hPrP Microhemorrhages,b,c albumin perivascular deposits, immunoglobulin extravasation, endothelial degeneration 5 and 11 mo Cortex, hippocampus, thalamus Kumar-Singh et al., 2005  3–6 mo 10 mo 3 mo Kumar-Singh et al., 2005  
APPSwFlLo; PSEN1M146L/L286V (5xFAD or Tg6799), hAPP695, K670M/N671L/I716V/V717I, mThy1, PSEN1 M146L/L286V, mThy1 IgG perivascular deposits 9 and 10 mo; not studied before 9 mo Cortex Park et al., 2017  2 mo Not studied 4–5 mo Oakley et al., 2006; Webster et al., 2014  
 Loss of LRP1 endothelial expression 7 mo; not studied before 7 mo Cortex Storck et al., 2016      
 Loss of GLUT1 endothelial expression, increased RAGE vascular expression, increased MMP-9 vascular expression, loss of BBB tight junctionsa,d,f 8 mo; not studied before 8 mo Cortex Kook et al., 2012      
Tg PSEN1 models         
PSEN1−/− Microhemorrhages,e endothelial degeneration E18.5 Neocortex Wen et al., 2005  Not studied Not studied Not studied (perinatal lethality) Wen et al., 2005  
PSEN1M146V Microhemorrhages,e basement membrane degeneration 10 and 37 mo Cortex, hippocampus Gama Sosa et al., 2010  24 mo No CAA Not studied Chen et al., 2000  
Tg tau models         
TetO-TauP301L (rTg4510), hMAPT P301L, tetracycline-responsive promoter BBB leakage of Evans blue, IgG perivascular deposits, microhemorrhages,e leukocyte infiltration 9 and 12 mo Cortex and hippocampus Blair et al., 2015  No Aβ pathology; Tau pathology 12 mo None Not studied Blair et al., 2015  
Tg pericyte-deficient models         
Pdgfrβ+/− Loss of pericytes, IgG perivascular deposits, fibrin perivascular deposits, thrombin and plasmin brain extravasation, loss of BBB tight junctions,a,d brain extravasation of exogenous tracers 1, 6, 8, 14, and 16 mo Cortex, hippocampus Bell et al., 2010  Not studied Not studied 6–9 mo, +neurodegenerative changes, loss of neurons Bell et al., 2010; Kisler et al., 2017b  
PdgfrβF7/F7 Loss of pericytes, IgG perivascular deposits, fibrin perivascular deposits, thrombin and plasmin brain extravasation, loss of BBB tight junctions,a,d brain extravasation of exogenous tracers 6 and 8 mo; not studied before 6 mo Cortex, hippocampus Bell et al., 2010  Not studied Not studied 6–9 mo, +neurodegenerative changes, loss of neurons Bell et al., 2010  
 Fibrin perivascular deposits 1, 2, 3, 4, 8, and 12 mo Cortex, hippocampus, striatum Nikolakopoulou et al., 2017      
Mouse line, construct, promoterFindingsAgeRegionReferenceBrain AβCAANeurodegenerative and behavior changesReference
Tg APP models         
APPSw/0 (Tg2576), hAPP695, K670M/N671L, hPrP Fibrin perivascular deposits, BBB leakage of Evans blue 6 and 12 mo; not studied before 6 mo Cortex, hippocampus Paul et al., 2007  7–10 mo 9–12 mo 6–9 mo Hsiao et al., 1996; Domnitz et al., 2005; Kumar-Singh et al., 2005; Webster et al., 2014  
 Loss of BBB tight junctions,a LRP1 endothelial expression, PDGFRβ+ pericytes, VSMCs 18 mo; not studied before 18 mo Cortex Park et al., 2013a      
 IgG perivascular deposits, loss of CD13+ pericytes, endothelial degeneration 1, 3, 6, and 9 mo Cortex, hippocampus Sagare et al., 2013      
 IgG perivascular deposits, albumin perivascular deposits, microhemorrhages,b,c endothelial degeneration, pericyte degeneration, VSMC loss, swollen astrocytic end-feet 17 and 25 mo; not studied before 17 mo Cortex, hippocampus, thalamus Kumar-Singh et al., 2005      
 BBB leakage of Evans blue, BBB leakage of exogenous tracers 4 and 10 mo Cortex Ujiie et al., 2003      
 Loss of BBB tight junctionsa,d 18 and 24 mo; not studied before 18 mo Cortex, hippocampus Biron et al., 2011      
 Loss of LRP1 endothelial expression 4 and 6 mo Cortex, hippocampus, thalamus Deane et al., 2004      
 Increased RAGE vascular expression 9 mo; not studied before 9 mo Cortex, hippocampus Deane et al., 2003      
 Genetically increased LRP1 expression in brain microvessels 16 and 24 mo; not studied before 16 mo Cortex Bell et al., 2009  Slowed down Slowed down Not studied Bell et al., 2009  
APPSw/0; Pdgfrβ+/−, accelerated loss of pericytes IgG perivascular deposits, loss of CD13+ pericytes 1, 3, 6, and 9 mo Cortex, hippocampus Sagare et al., 2013  Accelerated, +tau pathology and loss of neurons Accelerated Accelerated Sagare et al., 2013  
APPSw/0; Slc2a1+/−, GLUT1 endothelial haploinsufficiency Fibrin perivascular deposits, IgG perivascular deposits, and loss of BBB tight junctions,a,d LRP1 endothelial expression, GLUT1 endothelial expression 2 wk and 1, 8–10, 12, and 16 mo Cortex, hippocampus Winkler et al., 2015  Accelerated, +loss of neurons Not studied Accelerated Winkler et al., 2015  
APPSw/0; mdr1a/b–/–, loss of Pgp endothelial function Loss of Pgp endothelial expression, BBB leakage of Pgp substrate, loss of LRP1 endothelial expression 2 and 3 mo Striatum, cortex, hippocampus Cirrito et al., 2005  Accelerated Not studied Not studied Cirrito et al., 2005  
APPSw/0; Picalm+/−, PICALM endothelial haploinsufficiency Loss of PICALM endothelial expression 3 mo Cortex, hippocampus Zhao et al., 2015b  Accelerated Accelerated Accelerated Zhao et al., 2015b  
APP V717F (PDAPP), hAPP full-length, V717F, PDGFb Fibrin perivascular deposits, BBB leakage of Evans blue 6 and 12 mo; not studied before 6 mo Cortex, hippocampus Paul et al., 2007  6–9 mo 10–12 mo 6 mo Paul et al., 2007; Webster et al., 2014  
PD-hAPP, hAPP minigene, V717F/K670M/N671L, PDGFb Blockade of RAGE 9 mo Cortex, hippocampus Deane et al., 2003  Slowed down Not studied Not studied Deane et al., 2003  
APPSwI (TgCRND8), hAPP695, K670M/N671L/V717F, hPrP Fibrin perivascular deposits, BBB leakage of Evans blue 6 and 12 mo; not studied before 6 mo Cortex, hippocampus Paul et al., 2007  3 mo 6–7 mo 3 mo Domnitz et al., 2005; Webster et al., 2014  
 Fibrin perivascular deposits 6 mo; not studied before 6 mo Cortex Chen et al., 2017      
APPSwDI, hAPP770, K670M/N671L/E693Q/D694N, mThy1 Albumin perivascular deposits 6 mo; not studied before 6 mo Dorsal subiculum Kruyer et al., 2015  3–6 mo 6 mo 3–6 mo Davis et al., 2004; Deane et al., 2004  
 Loss of LRP1 endothelial expression 4 and 6 mo Cortex, hippocampus, and thalamus Deane et al., 2004      
 Genetically decreased LRP1 expression in brain microvessels 16 and 24 mo; not studied before 16 mo Cortex Bell et al., 2009  Accelerated Accelerated Not studied Bell et al., 2009  
APPSw (APP23), hAPP751, K670M/N671L, mThy1 Microhemorrhages,b,c leukocyte infiltration 16 and 30 mo; not studied before 16 mo Cortex, thalamus Beckmann et al., 2011  6 mo 12 mo 3 mo Webster et al., 2014  
TetO-APPSwI, hAPP695, K670M/N671L/V717F, tetracycline-responsive promoter Microhemorrhages,b,c increased BBB permeability to iodinated contrast agent 14 mo; not studied before 14 mo Cortex, hippocampus, thalamus Tanifum et al., 2014  2–6 mo 14 mo Not studied Tanifum et al., 2014  
APPSwArc (ArcAβ), hAPP695, K670M/N671L/E693G, mPrP Microhemorrhagese and increased BBB permeability to gadolinium contrast agent 9 and 21 mo; not studied before 9 mo Cortex, hippocampus, olfactive bulb Klohs et al., 2011, 2013   6 mo 9–15 mo 6 mo Klohs et al., 2012  
APPSw/0; PSEN1ΔE9, m/hAPP695 K595N/M596L × hPSEN1dE9, mPrP Microhemorrhagesb,c 9 mo; not studied before 9 mo Cortex Kelly et al., 2015  6–7 mo 6 mo 6 mo Duff et al., 1996; Webster et al., 2014  
 Fibrin perivascular deposits 10 mo; not studied before 10 mo Hippocampus, periventricular zone McManus et al., 2017      
APPSw/0; PSEN1M146L, hAPP695 K670M/N671L × PSEN1 M146L, hPrP Microhemorrhages,b,c albumin perivascular deposits, immunoglobulin extravasation, endothelial degeneration 5 and 11 mo Cortex, hippocampus, thalamus Kumar-Singh et al., 2005  3–6 mo 10 mo 3 mo Kumar-Singh et al., 2005  
APPSwFlLo; PSEN1M146L/L286V (5xFAD or Tg6799), hAPP695, K670M/N671L/I716V/V717I, mThy1, PSEN1 M146L/L286V, mThy1 IgG perivascular deposits 9 and 10 mo; not studied before 9 mo Cortex Park et al., 2017  2 mo Not studied 4–5 mo Oakley et al., 2006; Webster et al., 2014  
 Loss of LRP1 endothelial expression 7 mo; not studied before 7 mo Cortex Storck et al., 2016      
 Loss of GLUT1 endothelial expression, increased RAGE vascular expression, increased MMP-9 vascular expression, loss of BBB tight junctionsa,d,f 8 mo; not studied before 8 mo Cortex Kook et al., 2012      
Tg PSEN1 models         
PSEN1−/− Microhemorrhages,e endothelial degeneration E18.5 Neocortex Wen et al., 2005  Not studied Not studied Not studied (perinatal lethality) Wen et al., 2005  
PSEN1M146V Microhemorrhages,e basement membrane degeneration 10 and 37 mo Cortex, hippocampus Gama Sosa et al., 2010  24 mo No CAA Not studied Chen et al., 2000  
Tg tau models         
TetO-TauP301L (rTg4510), hMAPT P301L, tetracycline-responsive promoter BBB leakage of Evans blue, IgG perivascular deposits, microhemorrhages,e leukocyte infiltration 9 and 12 mo Cortex and hippocampus Blair et al., 2015  No Aβ pathology; Tau pathology 12 mo None Not studied Blair et al., 2015  
Tg pericyte-deficient models         
Pdgfrβ+/− Loss of pericytes, IgG perivascular deposits, fibrin perivascular deposits, thrombin and plasmin brain extravasation, loss of BBB tight junctions,a,d brain extravasation of exogenous tracers 1, 6, 8, 14, and 16 mo Cortex, hippocampus Bell et al., 2010  Not studied Not studied 6–9 mo, +neurodegenerative changes, loss of neurons Bell et al., 2010; Kisler et al., 2017b  
PdgfrβF7/F7 Loss of pericytes, IgG perivascular deposits, fibrin perivascular deposits, thrombin and plasmin brain extravasation, loss of BBB tight junctions,a,d brain extravasation of exogenous tracers 6 and 8 mo; not studied before 6 mo Cortex, hippocampus Bell et al., 2010  Not studied Not studied 6–9 mo, +neurodegenerative changes, loss of neurons Bell et al., 2010  
 Fibrin perivascular deposits 1, 2, 3, 4, 8, and 12 mo Cortex, hippocampus, striatum Nikolakopoulou et al., 2017      

APP, amyloid precursor protein; CAA, cerebral amyloid angiopathy; GLUT1, glucose transporter 1; hPrP, hamster prion promoter; IgG, immunoglobulin G; LRP1, low-density lipoprotein receptor-related protein 1; MAPT, microtubule-associated protein tau; MMP-9, matrix metalloproteinase-9; mPrP, mouse prion promoter; mThy1, mouse thymus cell antigen 1 promoter; PDGFRβ, platelet-derived growth factor receptor β; Pgp, P-glycoprotein; PICALM, phosphatidylinositol binding clathrin assembly protein; PSEN1, presenilin 1; RAGE, receptor for advanced glycation end products; VSMC, vascular smooth muscle cell.

a

Loss of BBB tight junctions as shown by high-resolution confocal microscopy analysis.

b

Microhemorrhages (hemosiderin deposits) at the capillary level.

c

Microhemorrhages (hemosiderin deposits) at the arteriolar level.

d

Loss of BBB tight junctions as shown by immunoblotting of isolated brain capillaries.

e

The exact vascular location is difficult to determine.

f

Loss of BBB tight junctions as shown by electron microscopy analysis.

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